Anti-fungal and anti-bacterial histatin-based peptides

ABSTRACT

Histatin-based peptides representing defined portions of the amino acid sequences of naturally occurring human histatins and methods for treatment of fungal or bacterial infection are described. These histatin-based peptides represent the active anti-fungal and anti-bacterial region of naturally occurring human histatins.

GOVERNMENT SUPPORT

The invention described herein was supported in whole or in part byGrant No. DE07652 from the National Institutes of Health, which havecertain rights in the invention.

RELATED APPLICATIONS

This Application is a Continuation-in-Part of and claims priority toU.S. Ser. No. 08/481,888, filed Jun. 7, 1995, now U.S. Pat. No.5,631,228 which is a Continuation-in-Part of U.S. Ser. No. 08/287,717,filed Aug. 9, 1994, now U.S. Pat. No. 5,486,503 which is a File WrapperContinuation of U.S. Ser. No. 08/145,030, filed Oct. 28, 1993 (nowabandoned), which is a File Wrapper Continuation of U.S. Ser. No.07/786,571, filed Nov. 1, 1991 (now abandoned), the contents of whichare incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The family of naturally occurring human histatins is a group of twelvelow molecular weight, abundant in histidine, peptides found in humansubmandibular and parotid salivary secretions (Oppenheim et al. (1986),J. Biol. Chem. 261: 1177-1182; Oppenheim et al. (1988), J. Biol. Chem.263: 7472-7477; Troxler et al. (1990), J. Dent. Res. 69: 2-6). Theprimary structure of the major family members (histatins 1, 3, and 5;70-80% of the whole family) has shown that these proteins consist of 38,32 and 24 amino acid residues, respectively. There is a high degree ofhomology among these three major histatins. Histatin 5 results frompost-translational cleavage of histatin 3. Many of the smaller membersof the histatin family may also, in fact, originate bypost-translational proteolysis of histatins 1, 3 and 5 (Oppenheim et al.(1989), Human Saliva: Clinical Chemistry and Microbiology Vol. 1 CRCPress, Boca Raton, Fla., ed. Tenovuo, J. O.; Lal et al. (1992), Arch.Oral Biol. 37: 7-13). The genes that encode histatins 1 and 3 have beenlocalized chromosomally (vanderspek et al., (1989), Am. J. Hum. Genet.45: 381-387) and sequenced (Sabatini, L. M. et al. (1989), Biochem.Biophys. Res. Comm. 160:495-502). Histatins 1 and 3 appear to be derivedfrom separate genes.

The three major human histatins exhibit specific antimicrobialactivities towards diverse oral microbiota. These histatins, atphysiological concentrations, are capable of killing Candida albicans inboth blastopore and mycelial forms (Pollock, J. J. et al. (1984),Infect. Immun. 44:702-707; Xu, T. et al. (1991), Infect. Immun. 59 (8):2549-2554). Histatins are also capable of killing oral bacteria,including Streptococcus mutans (MacKay, B. J. et al. (1984), Infect.Immun. 44:695-701; Xu, T. et al. (1990), J. Dent. Res. 69: 239),Porphyromonas gingivalis (Colon et al. (1993), J. Dent. Res. 72: 322)and Actinomyces viscosus (Kalpidis et al. (1992) J. Dent. Res. 72: 305).

Infection with the yeast Candida albicans is a prevalent and, in somecases, life-threatening condition affecting otherwise healthy andimmuno-compromised patients. Candidal vaginitis is estimated to affect15 to 55% of healthy young women. Candidal infections often occur indiabetics, during pregnancy, and following medication with antibiotics,steroid hormones, or oral contraceptives. (Tapper-Jones, L. M. et al.(1981) J. Clin. Pathol. 34:706-11; Sobel, J. D. et al. (1984) Infect.Immun. 44:576-580). Oral candidiasis is an early opportunistic infectionof Acquired Immune Deficiency Syndrome (AIDS) in individuals infectedwith human immunodeficiency virus type 1, as well as a complication ofradiation and chemotherapy in cancer patients. (Yeh, C.-K. et al.,(1988) J. of Acquired Immune Deficiency Syndromes 1:361-366). Inaddition, candidal infection of denture wearers plays a primary role indental stomatitis, a prevalent oral problem among the elderly. (Pollock,J. J. et al. (1990) NYS Dental J. 56:36-38). Candidal infections of skinand urethra are widespread problems. In patients in intensive care andimmuno-compromised patients, systemic fungal infection often leads todeath, since there are few safe and effective anti-fungalpharmaceuticals for intravenous use. (Burnie, J. P. et al. (1985)British Medical Journal 290:746-748). Similarly, infections with variousbacterial species can cause severe disease states and even death.

Although several anti-fungal agents (e.g., clotrimazole, miconazole,ketoconazole, and nystatin) and anti-bacterial agents (penicillin,streptomycin, tetracycline and chlorhexidine) are currently available,these agents are not completely effective, can lead to drug resistantorganisms and can produce adverse side effects. Many are not appropriatefor oral or systemic administration. Thus, a potent, naturally occurringanti-fungal or anti-bacterial substance would provide a significantimprovement in the treatment of microbial infection.

SUMMARY OF THE INVENTION

This invention is based on substantially pure peptides which haveanti-candidal or anti-bacterial activity which are equivalent to that ofnaturally occurring histatins but are smaller in size. These peptidesrepresent defined portions of the amino acid sequences of naturallyoccurring human histidine-rich salivary proteins called histatins, whichwill be referred to herein as histatin-based peptides. Thehistatin-based peptides of this invention also include defined portionsof the amino acid sequences of histatins with specific amino acidsubstitutions at specified positions of the sequences. As demonstratedherein, these histatin-based peptides have been shown to be superior,particularly on a weight basis, in anti-candidal or anti-bacterialactivity over the naturally occurring histatins. Thus, this inventionprovides compositions for treatment of fungal or bacterial infectioncomprising histatin-based peptides with defined amino acid sequences.These peptides are derived from a specific histatin-based peptide havinga specified 12 amino acid sequence. This peptide is designated aspeptide 113 (SEQ ID NO: 18). Other peptides with significant anti-fungalor anti-bacterial activities have sequence portions of at least 8 aminoacids from this histatin-based peptide or are homologs of peptide 113with amino acid substitutions at particular positions in the peptide.

BRIEF DESCRIPTION OF FIGURES

FIGS. 1A-1D shows the amino acid sequences of human histatins andpeptides 101, 102, 103, 104, 105, 113, 113-F4, 113-F5, 113-F12,113-F4.5, 113-F4.5.12, 113-K6, 113-H8, 113-K6H8, 113-F8, 113-L4.5.12,113-Y4.5.12, 113-Q2.10, 113-Q3.9, 113-Q2-3.9.10, 117, 118, 119, 120 and129.

FIG. 2 is a graph that shows the % killing of C. albicans blastoconidiaas a function of the concentration of histatin-5, peptide 103, peptide113 and peptide 129.

FIG. 3 is a graph that shows the % killing of C. Albicans blastoconidiaas a function of concentration of peptide 113, peptide 113-F4, peptide113-F5, peptide 113-F12, peptide 113-F4.5 and peptide 113-F4.5.12.

FIG. 4 is a graph that shows the % killing of C. albicans blastoconidiaas a function of concentration of peptide 113, peptide 113-K6, peptide113-H8, peptide 113-K6H8, peptide 113-F8, peptide 113 with an acetylgroup on the N-terminus (NA) and peptide 113 with a carbamyl group onthe N-terminus (NC).

FIG. 5 is a graph that shows the % killing of C. albicans blastoconidiaas a function of concentration of peptide 113, peptide 113-L4.5.12,peptide 113-Y4.5.12, peptide 113-Q2.10, peptide 113-Q3.9 and peptide113Q2.3.9.10.

FIG. 6 is a graph that shows the % killing of C. albicans blastoconidiaas a function of concentration of peptide 113 and peptide 113-F4.5.12 atpH 7.4 and at pH 4.0.

FIG. 7 is a graph that shows the amount of growth inhibition of P.gingivalis as a function of time for histatin 5, peptide 103, peptide113 and peptide 129, as well as when no histatin-based peptide ispresent.

FIG. 8 is a graph that shows the % killing of P. aeruginosa as afunction of concentration of peptide 113, peptide 113-K6, peptide113-H8, peptide 113-K6H8, peptide 113-F4.5.12 and peptide 113 with anacetyl group on the N-terminus (NA).

FIG. 9 is a graph that shows the % killing of P. aeruginosa as afunction of concentration of peptide 113, peptide 113-Y4.5.12, peptide113-L4.5.12, peptide 25 113-Q2.10, peptide 113-Q3.9 and peptide113-Q2.3.9.10.

FIG. 10 is a graph that shows the % inhibition of clostripain activityas a function of the concentration of histatin 5, peptide 101, peptide103, peptide 105, peptide 118, peptide 119, peptide 120 and peptide 129.

FIG. 11 is a graph that shows the % inhibition of clostripain activityas a function of the concentration of peptide 113 and peptide113-F4.5.12.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to peptides,which have anti-fungal oranti-bacterial activity, in which the amino acid sequences representdefined portions of the amino acid sequences of naturally occurringhuman histidine-rich salivary proteins called histatins. (Histatins arealso referred to in the literature as histidine-rich proteins or HRPs.)Histatins are major salivary proteins which are synthesized in theparotid and submandibular-sublingual secretory glands of humans and OldWorld monkeys. (Azen, E. A. (1978) Biochem. Genet. 16:79-99). Histatinsare believed to be part of an extraimmunologic defense system of theoral cavity. The anti-fungal activity of histatins, as well as theirinhibitory effect on several oral bacteria (such as the cariogenicStreptococcus mutans and the periodontal pathogen Porphyromonasgingivalis), have been demonstrated in vitro. In addition, theobservation that polyhistidine peptides inactivate herpes simplex virusin vitro and that whole saliva contains inhibitors of humanimmunodeficiency virus suggests the possibility that histatins may haveanti-viral activity. These in vitro studies support potential clinicaluse of compositions containing histatins or histatin-based peptides forthe treatment of local and systemic candidal infection, oral bacterialdiseases, such as caries and periodontitis, systemic bacterial infectionand viral infection. vaginal, urethral, mucosal, respiratory, skin, ear,oral or ophthalmic fungal or bacterial infections are particularlysusceptible to histatin-based peptide therapy. Microbes which arespecifically amenable to histatin-based peptide therapy are:

a) Candida albicans;

b) Actinomyces actinomycetemcomitans;

c) Actinomyces viscosus;

d) Bacteroides forsythus;

e) Bacteriodes fragilis;

f) Bacteriodes gracilis;

g) Bacteriodes ureolyticus;

h) Campylobacter concisus;

i) Campylobacter rectus;

j) Campylobacter showae;

k) Campylobacter sputorum;

l) Capnocytophaga gingivalis;

m) Capnocytophaga ochracea;

n) Capnocytophaga sputigena;

o) Clostridium histolyticum;

p) Eikenella corrodens;

q) Eubacterium nodatum;

r) Fusobacterium nucleatum;

s) Fusobacterium periodonticum;

t) Peptostreptococcus micros;

u) Porphyromonas endodontalis;

v) Porphyromonas gingivalis;

w) Prevotella intermedia;

x) Prevotella nigrescens;

y) Propionibacterium acnes;

z) Pseudomonas aeruginosa;

aa) Selenomonas noxia;

bb) Staphylococcus aureus;

cc) Streptococcus constellatus;

dd) Streptococcus gordonii;

ee) Streptococcus intermedius;

ff) Streptococcus mu tans;

gg) Streptococcus oralis;

hh) Streptococcus pneumonia;

ii) Streptococcus sanguis;

kk) Treponema denticola;

ll) Treponema pectinovorum;

mm) Treponema socranskii;

nn) Veillonella parvula; and

oo) Wolinella succinogenes.

The human histatin proteins have been isolated and sequenced. They havebeen shown to be a family of twelve related low molecular weightproteins. Comparison of the amino acid sequences of the histatinssuggests that histatin 2 and histatins 4-12 may have originated fromspecific proteolytic cleavage of histatin 1 and histatin 3,respectively. (Oppenheim, F. G. et al. (1988), J. Biol. Chem.263:7472-77; Troxler, R. F. et al. (1990), J. Dent. Res. 69(1):2-6).Cloning and sequence analysis of histatin cDNAs further suggest that thehistatins are encoded by two homologous genetic loci, whose primaryproducts are histatins 1 and 3. (Sabatini, L. M. et al. (1989), Biochem.Biophys. Res. Comm. 160:495-502; Vanderspek, J. C. et al. (1990), Arch.Oral Biol. 35(2):137-43).

The amino acid sequences of the anti-fungal and anti-bacterial peptidesof this invention represent all or defined portions of the amino acidsequence of peptide 113 (SEQ ID NO: 18). In addition, the anti-fungaland anti-bacterial peptides of this invention include all or definedportions of peptide 113 (SEQ ID NO: 18) with amino acid substitutions atparticular positions of the peptide.

Preferred embodiments of this invention are peptide 113 itself (SEQ IDNO: 18); fragments of peptide 113 containing at least an 8 amino acidsequence from this peptide; an amino acid sequence of at least 8 aminoacids from peptide 113 where the glycine at position 6 is replaced bylysine, arginine or another basic amino acid; an amino acid sequence ofat least 8 amino acids from peptide 113 where the lysine at position 8is replaced by histidine, phenylalanine or another hydrophobic aminoacid; an amino acid sequence of at least 8 amino acids from peptide 113where one or more of the histidines at positions 4, 5 and 12 is (are)replaced by phenylalanine, tyrosine, leucine or another hydrophobicamino acid; an amino acid sequence of at least 8 amino acids frompeptide 113 where one or both of the lysines at positions 2 and 10 is(are) replaced by glutamine, arginine or a combination of glutamine andarginine (when both lysines are replaced); and an amino acid sequence ofat least 8 amino acids from peptide 113 where one or both of thearginines at positions 3 and 9 is (are) replaced by glutamine, lysine ora combination of glutamine and lysine (when both arginines arereplaced). Combinations of these amino acid replacements in an aminoacid sequence of at least 8 amino acids from peptide 113 are allpreferred embodiments of the invention provided that a combination of 4glutamines or any other group of 4 non-basic amino acids at positions 2,3, 9 and 10 does not occur.

Specific preferred embodiments of this invention are peptide 113 itself(SEQ ID NO: 18), histatin 11 (SEQ ID NO: 11), peptide 129 (SEQ ID NO:23), peptide 117 (SEQ ID NO: 19), peptide 118 (SEQ ID NO: 20), peptide119 (SEQ ID NO: 21), peptide 120 (SEQ ID NO: 22), peptide 113-F4 (SEQ IDNO: 24), peptide 113-F5 (SEQ ID NO: 25), peptide 113-F12 (SEQ ID NO:26), peptide 113-F4.5 (SEQ ID NO: 27), peptide 113-F4.5.12 (SEQ ID NO:28), peptide 113-K6 (SEQ ID NO: 29), peptide 113-H8 (SEQ ID NO: 30),peptide 113-K6H8 (SEQ ID NO: 31), peptide 113-F8 (SEQ ID NO: 32),peptide 113-L4.5.12 (SEQ ID NO: 33), peptide 113-Y4.5.12 (SEQ ID NO:34), peptide 113-Q2.10 (SEQ ID NO: 35), and peptide 113-Q3.9 (SEQ ID NO:36). The amino acid sequences of these preferred peptides are shown inFIG. 1A-1D. Combinations of two or more of these peptides are alsoeffective as anti-fungal or anti-bacterial compositions and are includedas compositions of the invention. However, the combination of thesepeptides where glutamine occurs at positions 2, 3, 9 and 10, i.e.peptide 113-Q2.3.9.10 (SEQ ID NO: 37) is not a specifically preferredembodiment.

The peptides can be obtained from a naturally occurring source ofhistatin or they can be chemically synthesized or obtained byrecombinant DNA techniques as expression products from cellular sources.These peptides can be altered by minor chemical modifications, such asby adding small substituents or by modifying one or more of the covalentbonds within or between the amino acid residues, without significantlydiminishing the anti-fungal or anti-bacterial activities of thepeptides. Quite useful modifications are the addition of a substituentto either the amino terminus, the carboxyl terminus or to both ends ofthe peptide. These substituent addition modifications appear tostabilize the peptide in its active form and to aid in the prevention ofenzymatic degradation of these peptides. These substituent groups areadded to the amine, at the amino terminus, or to the carboxyl group, atthe carboxyl terminus. The substituent groups can be somewhat bulky andmay include one or more natural or modified amino acids. Particularlyuseful modifications are acetylation or carbamylation of the aminoterminus of the peptide or amidation of the carboxyl terminus of thepeptide. A combination of both modifications is especially useful. Suchmodifications appear to increase the biological half-life of thepeptides before degradation, encapsulation, internalization or excretionoccurs.

The peptides described herein were tested in assays designed to measureseparately their effectiveness in killing of blastoconidia of C.albicans in inhibiting the growth of P. gingivalis, in inhibitinghemagglutination caused by B. forsythus, and in inhibiting clostripainactivity. These assays are indicative of anti-fungal and anti-bacterialactivities of the histatin-based peptides of the present invention. Whentested in these assays, the histatin-based peptides of this inventionwere found surprisingly to have superior anti-candidal andanti-bacterial activity, particularly on an equivalent weight basis,when compared with histatin 5 as well as with histatin-based peptides101-105. These anti-fungal and anti-bacterial activities are surprisingin view of their size and truncated peptide form.

The following is a description of the histatin-based peptides, theantifungal activities of the histatin-based peptides as measured inassays for killing of Candida blastoconidia, and the anti-bacterialactivities of the histatin-based peptides as measured in assays forinhibition of P. gingivalis growth, inhibition of hemagglutinationcaused by B. forsythus and inhibition of clostripain enzyme activity.

Histatin 5 and Histatin-Based Peptides

Histatin 5 and the histatin-based peptides 101, 102, 103, 104, 105, 111,113, 113-F4, 113-F5, 113-F12, 113-F4.5, 113-F4.5.12, 113-K6, 113-H8,113-K6H8, 113-F8, 113-L4.5.12, 113-Y4.5.12, 113-Q2.10, 113-Q3.9,113-Q2.3.9.10, 117, 118, 119, 120 and 129 were chemically synthesized.The amino acid sequences of histatin 5 and the synthesizedhistatin-based peptides are shown in FIG. 1A-1D.

Anti-Fungal Activities of Histatin-Based Peptides

C. albicans is a dimorphic yeast. It can exist in a yeast orblastoconidial form, which upon germination develops into the hyphal orgerminated form. While the germinated form is considered to be moreinvasive, most of the C. albicans isolates harvested from the oralcavities of healthy individuals appear to be in the blastoconidial form.(Arendorf, T. M. et al. (1980), Arch. Oral Biol. 25:1-10; Gow, N.A.R. etal. (1987), Criti. Rev. Microbiol. 15:73-78; Odds, F. C. (1988), Candidaand Candidosis, 2nd ed., Bailliere Tindall, London, England).Anti-fungal activity of synthetic histatin 5, histatin-based peptide113, peptides based on portions of the amino acid sequences ofhistatin-based peptide 113 and peptides derived from histatin-basedpeptide 113 with specified amino acid substitutions was measured inassays designed to test the effectiveness of the peptides against theblastoconidia form of Candida (Table 1). These assays, which measurekilling of blastoconidia of C. albicans, are described in Xu et al.,which is herein incorporated by reference. (Xu, T. et al. (1991),Infect. Immun. 59(8):2549-2554). Peptide 113 was found to be aboutequipotent with histatin 5, demonstrating its anti-fungal activitydespite its size in comparison with histatin 5. Peptides 101-105demonstrated fungicidal activity comparable to that of histatin 5 andhistatin-based peptide 113. Histatin 11, peptides 117-120 and peptide129 all have demonstrable fungicidal activity even though they aresmaller than peptide 113. These latter peptides appear to have the aminoacid sequences of peptide 113 (and histatin 5) which are required foranti-fungal activity. The anti-fungal potency of the histatin-basedpeptide appears to be a function of both the size and the amino acidsequence of the respective peptide. In particular, the anti-fungalpotency of human histatins appears to reside in peptide 113 withselected subpeptides of peptide 113 maintaining at least partialanti-fungal activity.

Modifications of peptide 113 by making particular types of amino acidsubstitutions in this peptide result in peptides that retain anti-fungalactivity and in many instances display enhanced anti-fungal activity incomparison to peptide 113. For example, replacements of histidine withphenylalanine at positions 4, 5 or 12, either singly or in combination,result in peptides with increased anti-fungal activities in comparisonto peptide 113. Likewise, replacements of the glycine with lysine atposition 6 or the lysine with histidine or phenylalanine at position 8,either singly or in combination, result in other peptides withnoticeably increased fungicidal activities in comparison to peptide 113.Acetylation or carbamylation of the N-terminus of peptide 113 alsoyields modified peptide 113 peptides with significant anti-fungalactivity.

An additional feature of the directed amino acid substitutions ofpeptide 113 is that particular types of amino acid substitutions resultin peptides with enhanced activities, e.g. anti-fungal, at a pH otherthan neutral. For example, the substitution of histidine withphenylalanine at positions 4, 5 and 12 resulted in peptides withsignificant anti-fungal activity at pH 4.0 while peptide 113 isessentially devoid of anti-fungal activity at this lower pH. Similarmodifications of the peptides of this invention, such as peptide 113, toallow the peptides to have anti-microbial activity at pHs other thanneutral values are included in the present invention.

Peptide sequences containing permutations of the amino acid sequences ofnative histatins and modified peptides can be produced by known methods,such as recombinant DNA techniques and solid-phase synthesis. Cloned DNAencoding the human histatins may be obtained as described by Sabatini etal. or Vanderspek et al., whose teachings are incorporated herein byreference. (Sabatini. L. M. et al. (1989), Biochem. Biophys. Res. Comm.160:495-502; Vanderspek, J. C. et al. (1990), Arch. Oral Biol.35(2):137-43). cDNA encoding the histatin-based peptides can be clonedby recombinant DNA techniques, for instance, by using degenerateoligonucleotides based on the amino acid sequence of the histatin-basedpeptides as primers for polymerase chain reaction amplification.Alternatively, oligonucleotides encoding histatins or histatin-basedpeptides can be synthesized chemically using commercially availableequipment. They can then be made double-stranded and cloned into vectorsfor amplification in prokaryotic or eukaryotic host cells.

Histatin-based peptides can be produced in a variety of expressionvector/host systems, which are available commercially or can bereproduced according to recombinant DNA and cell culture techniques. Thevector/host expression systems can be prokaryotic or eucaryotic, and caninclude bacterial, yeast, insect, mammalian, and viral expressionsystems. The construction of expression vectors encoding histatin-basedpeptides, transfer of the vectors into various host cells, andproduction of peptides from transformed host cells can be accomplishedusing genetic engineering techniques, as described in manuals such asMolecular Cloning and Current Protocols in Molecular Biology, whoseteachings are incorporated herein by reference. (Sambrook, J., Fritsch,E. F. and Maniatis, T. (1989), Molecular Cloning, 2nd ed., Cold SpringHarbor Laboratory Press; Ausubel, F. M. et al., eds., Current Protocolsin Molecular Biology, New York; Greene Publishing Associates andWiley-Interscience)

Modified histatin based peptides, such as particular amino acidsubstitutions of peptide 113, can be synthesized chemically, or beproduced from cloned DNAs containing mutated nucleotide sequences.Histatin-based peptides encoded by expression vectors may be modifieddue to post-translational processing in a particular expressionvector/host cell system. (See, e.g., Wold, F. (1981), Ann. Rev. Biochem.50:783-814). Histatin-based peptides may also be modified by chemicalalteration of amino acid side-chain groups, or by other covalentmodification. (See, e.g., Glazer, A. N. et al. (1975), ChemicalModification of Proteins, North Holland; Katre, N. V. et al. (1987),Proc. Natl. Acad. Sci. USA 84:1487)

Therapeutic Applications

The histatin-based peptides of this invention, representing definedportions of the amino acid sequence of histatin-based peptide 113:peptide 113 itself, histatin 11, peptide 117, peptide 118, peptide 119,peptide 120 and peptide 129, and modified peptide 113 such as peptide113-F4, peptide 113-F5, peptide 113-F12, peptide 113-F4.5, peptide113-F4.5.12, peptide 113-K6, peptide 113-H8, peptide 113-K6H8, peptide113-F8, peptide 113-L4.5.12, peptide 113-Y4.5.12, peptide 113-Q2.10,peptide 113-Q3.9, can be used in compositions and methods of treatmentfor fungal, and in particular, candidal infection, or for bacterialinfection. These methods of treatment for fungal or bacterial infectionapply to preventive treatment as well. The compositions may containcombinations of histatin-based peptides, in order to obtain maximumactivity against all developmental forms of the fungus. The ionicstrength, presence of various mono- and divalent ions, and pH of thecompositions may be adjusted to obtain maximum anti-fungal oranti-bacterial activity of the histatin-based peptides, as described inXu et al. (Xu, T. et al. (1991), Infect. Immun. 59(8):2549-54). Carriersappropriate for administration of anti-fungal agents to the vagina, theurethra, the ear, the oral cavity, the respiratory system, theophthalmic region, various mucosal regions and skin are known, anddescribed, for instance, in U.S. Pat. No. 4,725,576 (FungicidalPolypeptide Compositions Containing L-His and Methods for Use Thereforby J. J. Pollock and B. J. MacKay, Feb. 16, 1988) . Compositions fortreatment of systemic infection can be administered by various routes,such as intravenously or subdermally.

Expression vectors encoding the above-mentioned peptides can be used incompositions and methods for anti-fungal or anti-bacterial treatment.Expression vectors may be administered in compositions which introducegenetic material encoding histatin-based peptides into cells of thepatients. For example, recombinant expression vectors based onretroviruses or adenovirus vaccines may be used to infect patients.

A method of anti-fungal or anti-bacterial therapy using theabove-described expression vectors is bacterial substitution therapy.Bacterial substitution therapy can be used to treat fungal or bacterialinfection of areas in the urinary/reproductive, respiratory and/orgastro-intestinal tracts of a patient. The therapy comprises thefollowing: 1) transforming a particular bacterium with DNA comprising anexpression vector which encodes a histatin-based peptide describedabove, thereby producing transformed cells; 2) selecting transformedcells which express the peptide encoded by the expression vector,thereby obtaining transformed cells which express a histatin-basedpeptide; and 3) administering transformed cells which express ahistatin-based peptide in an appropriate carrier to the infected area.

One application of bacterial substitution therapy is treatment of fungalor bacterial infections of the oral cavity. A number of species of theoral bacterial Streptococcus can be used as vehicles for the expressionvectors. For example, recombinant S. lactis has been used in oralimmunization of mice against a heterologous antigen. (Iwaki, M. et al.(1990), Infect. Immun. 58(9):2929-34). Other oral bacteria which can beused as vehicles for the expression vectors, plasmids for constructingexpression vectors capable of amplification in oral bacterial hostcells, transformation methods, and administration of compositionscontaining oral bacteria to humans have been described. (See, e.g.,Kuramitsu, H. K. et al. (1984), J. General Microbiology 130:2497-2500;LeBlanc, D. J. et al. (1978), Proc. Natl. Acad. Sci. USA75(7):3484-3487; Macrina, F. L. et al. (1980), J. Bacteriology143(3):1425-1435; Kuramitsu, H. K. et al. (1982), Infect. Immun.36(1):435-436; Svanberg, M. et al. (1984), Infect. Immun.43(3):817-821).

The compositions and methods for treatment of fungal or bacterialinfections discussed above are not limited to use in humans, but canhave veterinary applications as well.

Furthermore, the above-described compositions and methods for treatmentof fungal infection can also be used for treatment of bacterialinfections (e.g., of S. mutans, P. aeruginosa or P. gingivalis) andviral infections (e.g., of herpex simplex virus or humanimmunodeficiency virus type 1).

Hemagglutination Activity of Bacteria and Histatin Inhibition of thisActivity

Even though the association between hemagglutination activity andadherence on host cells in the oral environment is not clear, it isgenerally accepted that hemagglutination activity is an indicator forcolonizing ability of bacteria. Periodontal pathogens must adhere toother bacteria and host cells in order to express their noxiousdestructive potential upon periodontal tissues. Hemagglutinin is thoughtto be involved in bacterial colonization. Proteases such as collagenase,sialidase, and trypsin-like protease are involved in the degradation ofhost tissues, and low-molecular weight toxic products such as butyricand propionic acids which are cytotoxic are produced. In a similarfashion, B. forsythus has been shown to possess sialidase andtrypsin-like protease. Sialidase has the ability of altering the hostresponse to periodontal microorganisms. For instance, it cleaves sialicacid from erythrocytes and leukocytes which results in removal of thesecells from the circulation. It also decreases the ability of IgG to bindcomplement, decreases collagen production, and stimulates lymphocytes.Trypsin-like protease can cleave a variety of synthetic substrates. Itis so called because it can hydrolyse the synthetic substratebenzoyl-DL-arginine-naphylamide (BANA), used for detection of trypsinactivity. P. gingivalis, B. forsythus and T. denticola possess strongBANA hydrolase activity. B. forsythus also possesses hemagglutinin(s).

Ability for adherence on erythrocytes is of great importance in theinteractions of periodontal pathogens with the host. The close proximityof these bacteria with the host tissues as well as with erythrocytesthat bathe the periodontal pocket during progression of the disease,indicates multiple interrelations between these elements. Additionally,periodontal microbes require heme-containing products for their survivaland multiplication and this need dictates interactions with cells suchas erythrocytes that are rich in these compounds. P. gingivalis has beenshown to possess both hemagglutinin(s) and hemolysin that provideattachment on erythrocytes and utilization of heme-compounds.

It has been shown (Murakami et al. (1990) Arch. Oral Biol. 9:775) thathistatin 5 and histatin 8 inhibit hemagglutination of P. gingivalis 381.Complete hemagglutination inhibition was reported for histatin 5 at aconcentration of 5 nmole/ml. Thus, it appears that histatins and, moreimportantly, histatin-based peptides can play a role in inhibitingbacterial growth and deleterious activity in the periodontal region.

Clostripain Inhibition by Histatin-Based Peptides

Clostripain is an endopeptidase enzyme synthesized by Clostridiumhistolyticum. This enzyme, with its protein degradative activity, can beinhibited by histatin 5 and by histatin-based peptides (see Table 1).Thus, histatin-based peptides can inhibit bacterial function byinhibiting bacterial enzymes which are essential for the bacterialviability.

EXAMPLE 1. MATERIALS AND METHODS

A. Isolation and Chemical Svnthesis of Histatin-Based Peptides

Isolation and amino acid sequence determination of human histatins wereperformed as described in Oppenheim et al., whose teachings are hereinincorporated by reference. (Oppenheim, F. G. et al. (1988), J. Biol.Chem. 263(16):7472-7477). Human parotid secretion from healthy adultswas stimulated using sour lemon candies, collected with Curby cups inice-chilled graduated cylinders, pooled, dialyzed and lyophilized. Totalprotein in human parotid secretion was subjected to fractionation onBio-Gel P-2 (Bio-Rad Laboratories, Richmond, Calif.) developed in 0.05Mammonium formate buffer, pH 4.0. The protein fraction enriched withhistatins was further purified using reversed-phase high-performanceliquid chromatography on a C₁₈ column. Purified histatins wereevaporated to dryness, dissolved in deionixzed water, quantified byamino acid analysis, lyophilized, and stored at -20° C. until use.

Histatin-based peptides were synthesized by the solid phase method ofMerrifield. (Merrifield, B. (1986) Science 232:341-47). Peptides weresynthesized by a MilliGen/Bioresearch Sam-Two Peptide Synthesizer usingFmoc L-amino acid kits (Millipore, Bedford, Mass.) and purified on a TSKODS-i20T C₁₈ column (5 μm, 4.6×250 mm) using RP-HPLC (Pharmacia-LKB).The purified peptides were quantified by amino acid analysis on aBeckman System 6300 amino acid analyzer.

B C. albicans Killing

(1) C. albicans Stock

A well-described strain of C. albicans was used in the bioassay. Thisstrain, ATCC 44505, was originally isolated from the human oral cavity.Cultures were stored at 4° C. on Sabouraud dextrose agar plates (DifcoLaboratories, Detroit, Mich.) until use. Stationary phase growth cellswere obtained following growth at 30° C. for 18 h on Sabouraud dextroseagar plates. Colonies were harvested and suspended in 10 mM potassiumphosphate buffer (PPB), pH 7.4.

To initiate log phase growth, an aliquot of stock C. albicans wassuspended in Sabouraud dextrose broth (Difco) and incubated at 30° C. ina shaking water bath. The growth phase was determined by taking aliquotsof the culture at one hour intervals to monitor the optical density(O.D.) at 560 nm. Early log phase was obtained at 4 to 6 h, indicated byan O.D. of about 0.6. Log phase cells were harvested and utilized in theblastoconidia killing assay in a manner identical to that described forstationary phase cells. A final concentration of 10⁵ cells/ml (eitherstationary or log phase fungus) was used in all assays.

(2) Suspension Buffers

The standard suspension buffer utilized in the blastospore killing assaywas 0.01M PPB, pH 7.4. An alternate suspension buffer,N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acids (HEPES; SigmaChemical Co., St. Louis, Mo.), pH 7.4, can also be utilized.

(3) Bioassays

The following assay was used to evaluate the effects of histatins on thekilling of blastoconidia of C. albicans.

a. For the killing of blastoconidia assay, 50 μl aliquots of cells(2×10⁵ cells/ml) diluted in suspension buffer were allowed to attach toa polystyrene 96-well micro-titer plate (COSTAR, Cambridge, Mass.) for15 min at room temperature, and then incubated with an equal volume of ahistatin or histatin peptide in suspension buffer for 1 h at 37° C.Controls were carried out in the absence of the histatin or histatinpeptide. After incubation, wells were washed three times bycentrifugation at 1,000 xg for 5 min and covered with aliquots of moltenSabouraud dextrose broth (Difco) containing 2% agarose (Sigma) at 45° C.The plate was then incubated at 30° C. for 8 h. Under such conditions,live cells will divide and begin to form colonies, while dead cells willremain as single cells. To determine the percentage of blastoconidiakilled, a total of 100 single cells and/or colonies were counted under aNikon inverted microscope at 400× magnification and the extent ofkilling was calculated using the formula: 1-(number of colonies intreated sample)/(number of colonies in control)!×100%.

(4) Statistical Analysis

Data were obtained by calculating the mean and standard deviation fromtriplicate assays. From the dose response relationship, doses effectinga 50% killing (LD₅₀) were determined.

C. BACTERIAL GROWTH INHIBITION AND CELL KILLING ASSAYS

(1) Bacterial Strains and Culture Conditions

(a) The bacteria used in one investigation, Porphyromonas gingivalisstrain A7A1-28, is a typical key pathogenic organism associated withdestructive periodontal diseases. The bacteria were multiply subculturedin Enriched Todd Hewitt broth (ETHB, Difco Lab., Detroit, Mich.).Microorganisms were stored in the same broths containing 20% and 50%glycerol, at -20° C. and -70° C., respectively. These served as stockcultures from which all preparations originated.

Working stock cultures were maintained by weekly transfer to Brain HeartInfusion Anaerobic Sheep Blood Agar plates (BHIA, Becton Dickinson andCo., Cockeysville, Md.), and Trypticase Soy Anaerobic Sheep Blood Agarplates (TSA, Becton Dickinson and Co., Cockeysville, Md.). Plates wereincubated for 3 to 4 days under strictly anaerobic conditions. For thebacteriostatic assay, bacteria were collected from plates, inoculatedinto the aforementioned broth and grown at 37° C., under strictlyanaerobic conditions for 24 to 48 hours.

(b) Two other bacterial species were used in a bacterial cell killingassay system. These bacterial species were Streptococcus mutans strainSJ32 and Pseudomonas aeruginosa ATCC Accession Number 27853. The assayswere performed using liquid overnight cultures (nutrient broth for P.aeruginosa; Todd Hewitt broth for S. mutans) growth media from frozenstocks of these bacterial species. In the assay, the bacteria werediluted into assay buffer (10 mM Potassium Phosphate, pH 6.0 with 20 mMNaCl for P. Aeruginosa; and 10 mM Potassium Phosphate, pH 5.2 with 20 mMNaCl for S.mutans) to a concentration of 2×10⁵ cfu/ml (1×10⁹ cfu/OD/ml)and combined with an equal volume (250 μl) of peptide to produce 500 μlincubation mixture with a final concentration of 10⁵ cfu/ml. Concrolsconstituted buffer and bacteria but no peptide. After incubation at 37°C. (30 minutes incubation for P. aeruginosa; and 60 minutes incubationfor S. mutans), the mixtures were plated onto agar media (nutrient agarfor P. aeruginosa; and Todd Hewitt media with 0.5% glucose for S.mutans) and incubated at 37° C. until colonies developed. The meannumber of colonies was determined from a minimum of 4 plates and percentkilling was determined by comparing the colony number arising fromcontrol cultures versus the colony number arising frompeptide-containing assay mixtures.

(2) Microdilution Bacteriostatic Assay

A modification of the typical microdilution assay (Rotilie et al., 1975)for the determination of minimal inhibitory concentration (MIC) ofantimicrobial agents was utilized to investigate the bacteriostaticactivity of the peptides. A standardized bacterial inoculum (P.gingivalis) was exposed to serially diluted antimicrobial peptides in anenriched broth medium that was suitable for the growth of anaerobicbacteria. The test was adapted for use in the 96-well microtiter plates.Results with the microdilution method have been shown to be comparableto the other known techniques for antimicrobial susceptibility such asthe dilution method, the agar dilution method, and the broth-diskelution method (Rosenblatt et al., 1979). In the typical assay, themicrotiter plate was observed at multiple time points after incubationfor visible growth. The modification introduced here was based on thespectrophotometric reading of the microtiter plate after incubation.

Microorganisms from cultures maintained in the aforementioned plateswere inoculated into 5 ml of the above-mentioned broths and culturedovernight at 37° C. under strictly anaerobic conditions with continuousagitation on a minishaker (IKA-Labortechnik, Staufen i. Br., Germany).The bacteria were grown until reaching the late log phase and were thensuspended in the same broths to an optical density (O.D.) of 0.1 at 560nm. The peptides were diluted in 0.01M phosphate buffered saline (PBS),pH 7. Forty μl aliquots of peptide dilutions were added in each well ofa U-bottom microtiter plate (Costar, Cambridge, Mass.) to give finalconcentrations of 2000, 1000, 500 and 250 μM. Twenty μl of bacterialinoculum was added to all the wells. Finally, 100 μl of the suitablebroth were added to each well. The optical density of the wells of themicrotiter plate was determined using a microplate reader set at 550 nmand the plate was then incubated under strictly anaerobic conditions for24 hours. Controls were made by replacing the peptide dilutions with PBSalone. After the incubation, the mixtures in each well were mixedmanually to resuspend sedimented bacteria and the plate was read again.The experiments were conducted twice every time. The biologic activitywas calculated according to the formula:

100- (Fin ODexp-In ODexp)/(Fin ODctr-In ODctr)!×100!

where:

Fin ODexp is the OD of the final experimental group;

In ODexp is the OD of the initial experimental group;

Fin ODctr is the OD of the final control group; and

In ODctr is the OD of the initial control group.

In addition, the % increase in time to reach midlog phase growth wascalculated.

The data presentation represent the means (±SEM) of at least 2 separateexperiments.

D. INHIBITION OF HEMAGGLUTINATION ASSAYS

(1) Strains and Growth Conditions for Hemagglutination Assays

The P. gingivalis strain of Section C.(1) was also used for thehemagglutination assays. The bacterial growth and culture conditionswere also the same as those described in Section C.(1).

(2) Hemagglutination Assay

A classic assay was utilized to determine the hemagglutination potentialof the P. gingivalis strain. Microorganisms were inoculated into BFBbroth and cultured overnight, for approximately 24 hours at 37° C. understrictly anaerobic conditions with continuous agitation on a minishaker(IKA-Labortechnik, Staufen i. Br., Germany). The bacteria were harvestedby centrifugatin at 3,000 r.p.m. for 20 min, at 4° C., washed twice in0.01M phosphate buffered saline (PBS), pH 7.4, and suspended in the samebuffer to an optical density of 1.0 at 550 nm. Erythrocytes wereobtained from a young male with O-type blood, since no difference inhemagglutination was observed in preliminary experiments with differentABO blood groups. One ml of blood was drawn each time, washed twice inPBS at 1,000 r.p.m. for 10 min at 4° C. and suspended in the same bufferat a 2% (v/v) final concentration. Fifty μl of the bacterial suspensionwere serially diluted in PBS (two-fold steps) in a 96-well U-bottommicroplate (Costar, Cambridge, Mass.). Fifty μl of the erythrocytesuspension were added to each well. Controls without bacteria orerythrocytes were included. The microplate was slightly shaken andincubated at room temperature for 2 hours. Visible examination on awhite background was used to determine hemagglutination. The amount ofhemagglutination was rated as none,(-), moderate (+/-), or strong (+).Erythrocytes in control wells with PBS precipitated to the center of thewell, whereas erythrocyte-bacteria aggregates precipitated at theperiphery of the bottom. The hemagglutination titer was expressed as thereciprocal of the highest dilution of the bacterial suspension providingvisible hemagglutination.

(3) Histatin Peptide Inhibition of Hemagclutination Assay

Preparation of erythrocyte and bacterial suspensions were the same asfor the hemagglutination assay. Fifty μl of histatin peptide solutionswere diluted in PBS in a U-bottom microplate, at various two-foldconcentrations with 600 nmole/ml being the highest. The bacterialconcentration utilized was normally twice the minimal concentrationwhich gave strong hemagglutination. Equal volumes of the bacterialsuspension were poured into the wells containing the histatin peptides.Finally, 50 μl of erythrocyte suspension were added in each well. Themicroplate was slightly shaken and incubated at room temperature for 2hours. Controls were made by replacement of the peptide dilutions withPBS only. The experiments were conducted at least twice. The lowesthistatin peptide concentration without hemagglutination (completeinhibition) was determined upon visual examination. The highest finalhistatin peptide concentration utilized was 100 nmole/ml.

E. CLOSTRIPAIN ASSAYS

Clostripain from Clostridium histolyticum (Sigma Chemical Corp., St.Louis, Mo.) was dissolved in deionized water to a concentration of 1mg/mL (300 units/mg) and activated with the addition of 10 mmol/L DTT.To measure its hydrolytic activity, clostripain (6 units) was added to50 nmol/L Hepes buffer, pH 7.5, containing 80 gmol/L BAPNA(benzoyl-arginine-p-nitroanilide), together with 5.6 μmol/L of histatinpeptide inhibitor. As controls, assays were performed in the absence ofany histatin peptide inhibitor. The activity was monitored continuouslyat 405 nm using a Molecular Devices V_(Max) microtitre plate reader. Theactivities were determined from the maximum rates of substratehydrolysis. Assays were done in duplicate, and the means normalized tothe controls.

EXAMPLE 2. EFFECTS OF HISTATIN PEPTIDES ON FUNGAL OR BACTERIAL VIABILITY

FIGS. 2-11 and Table 1 summarize the results of the fungal killing,bacterial growth inhibition, bacterial cell killing, bacteria mediatedhemagglutination inhibition and bacterial enzyme (clostripain)inhibition effects of histatin 5 and several tested histatin peptides.For comparison purposes, the anti-fungal and anti-bacterial effects ofhistatin 11 and the histatin-based peptides other than amino acidsubstituted variants of peptide 113 were assessed with synthesizedhistatin 5 as a standard. The amino acid substituted variants of peptide113 were assessed for their anti-fungal and anti-bacterial effects withpeptide 113 as a standard.

Histatin 11 and histatin-based peptides 113, 117, 118, 119, 120 and 129have C. albicans blastoconidia killing, P. gingivalis growth inhibition,bacteria mediated hemagglutination inhibition and clostripain inhibitioneffects. The various modified peptide 113 variants, i.e. peptide 113-F4,peptide 113-F5, peptide 113-F12, peptide 113-F4.5, peptide 113-F4.5.12,peptide 113-K6, peptide 113-H8, peptide 113-K6H8, peptide 113-F8,peptide 113-L4.5.12, peptide 113-Y4.5.12, peptide 113-Q2.10,, peptide113-Q3.9, peptide 113 with an acetyl blocking group on the N-terminus ofthe peptide, and peptide 113 with a carbamyl blocking group on theN-terminus also exhibit anti-fungal and anti-bacterial activity. Theseantimicrobial effects are similar to those observed for histatin 5 andfor histatin-based peptides 101-105. Although expected variations existin anti-fungal and anti-bacterial effects between the tested peptides,the antimicrobial effects of the histatin-based peptides are comparableto those of histatin 5. These results demonstrate that thesehistatin-based peptides are efficacious as anti-fungal or anti-bacterialagents. In particular, these results demonstrate that histatin-basedpeptide 113 and its subpeptides histatin 11, histatin-based peptides117, 118, 119, 120 and 129 are more efficacious on the basis ofmolecular weight or amino acid sequence length than histatin 5. Theanti-fungal and anti-bacterial activity of the histatins appears to beconcentrated in the amino acid sequence of histatin-based peptide 113.Selected amino acid substitutions to form variants of peptide 113 alsoretain and often enhance the anti-fungal and anti-bacterial activity ofthe original peptide.

                  TABLE 1    ______________________________________    SUMMARY OF HISTATIN PEPTIDE SEQUENCES    AND BIOLOGICAL ACTIVITY TESTING    Histatin      C.    Peptide           MW     albicans P. gingivalis                                   Hemagglut                                           Clostripain    ______________________________________    SynHis5           3037   3.0    μM                             88.7%   3.12  μM                                               <6.2  μM    101    2025   3.5                1.56      7.5    102           10         +++    103    2613   4.5        56.6    1.56      19    104    2055   NA    105    2978   5.0        +++     6.25      3.3    His 11 1080   +                  100       NA    113    1563   5.8        34.95   25        25    117    1492   ++++    118    1426   ++++               6.25      45    119    1279   ++                 25        >50    120    1151   ++                 50        >50    129           27         15.4    50        19    ______________________________________     Key:     C. albicans: Results expressed as LD.sub.50 (μM) for % killing or %     killing at 50 μM dose (see below for scoring).     P. gingivalis: Results expressed as % increase in time to reach mid     logphase growth (0.2 OD) for the 2 mM dose or % inhibition at 500 μM     dose (see below for scoring).     Hemagglutination: Results expressed as lowest dose (μM) at which     hemagglutination was observed using P. Gingivalis.     Clostripain: Results expressed as IC.sub.50 (μM) for inhibition of     Clostripain.     Scoring: The highest response seen was used in the scoring.     ++++80-100%     +++50-80%     ++20-50%     +<20%     NA Not Active

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

    __________________________________________________________________________    #             SEQUENCE LISTING    - (1) GENERAL INFORMATION:    -    (iii) NUMBER OF SEQUENCES: 37    - (2) INFORMATION FOR SEQ ID NO:1:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 38 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (ix) FEATURE:              (A) NAME/KEY: Modified-sit - #e              (B) LOCATION: 2    #/note= "/product="PSE""RMATION:    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:    -      Asp Xaa His Glu Lys Arg His His - # Gly Tyr Arg Arg Lys Phe His    Glu    #   15    -      Lys His His Ser His Arg Glu Phe - # Pro Phe Tyr Gly Asp Tyr Gly    Ser    #                 30    -      Asn Tyr Leu Tyr Asp Asn                 35    - (2) INFORMATION FOR SEQ ID NO:2:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 27 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:    -      Arg Lys Phe His Glu Lys His His - # Ser His Arg Glu Phe Pro Phe    Tyr    #   15    -      Gly Asp Tyr Gly Ser Asn Tyr Leu - # Tyr Asp Asn    #                 25    - (2) INFORMATION FOR SEQ ID NO:3:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 32 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:    -      Asp Ser His Ala Lys Arg His His - # Gly Tyr Lys Arg Lys Phe His    Glu    #   15    -      Lys His His Ser His Arg Gly Tyr - # Arg Ser Asn Tyr Leu Tyr Asp    Asn    #                 30    - (2) INFORMATION FOR SEQ ID NO:4:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 21 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:    -      Arg Lys Phe His Glu Lys His His - # Ser His Arg Gly Tyr Arg Ser    Asn    #   15    -      Tyr Leu Tyr Asp Asn                     20    - (2) INFORMATION FOR SEQ ID NO:5:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 24 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:    -      Asp Ser His Ala Lys Arg His His - # Gly Tyr Lys Arg Lys Phe His    Glu    #   15    -      Lys His His Ser His Arg Gly Tyr                     20    - (2) INFORMATION FOR SEQ ID NO:6:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 25 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:    -      Asp Ser His Ala Lys Arg His His - # Gly Tyr Lys Arg Lys Phe His    Glu    #   15    -      Lys His His Ser His Arg Gly Tyr - # Arg    #                 25    - (2) INFORMATION FOR SEQ ID NO:7:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 13 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:    -      Arg Lys Phe His Glu Lys His His - # Ser His Arg Gly Tyr    #   10    - (2) INFORMATION FOR SEQ ID NO:8:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:    -      Lys Phe His Glu Lys His His Ser - # His Arg Gly Tyr    #   10    - (2) INFORMATION FOR SEQ ID NO:9:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 14 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:    -      Arg Lys Phe His Glu Lys His His - # Ser His Arg Gly Tyr Arg    #   10    - (2) INFORMATION FOR SEQ ID NO:10:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 13 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:    -      Lys Phe His Glu Lys His His Ser - # His Arg Gly Tyr Arg    #   10    - (2) INFORMATION FOR SEQ ID NO:11:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 8 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:    -      Lys Arg His His Gly Tyr Lys Arg    #  5 1    - (2) INFORMATION FOR SEQ ID NO:12:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 7 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:    -      Lys Arg His His Gly Tyr Lys    #  5 1    - (2) INFORMATION FOR SEQ ID NO:13:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 21 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:    -      Lys Arg His His Gly Tyr Lys Arg - # Lys Phe His Glu Lys His His    Ser    #   15    -      His Arg Gly Tyr Arg                     20    - (2) INFORMATION FOR SEQ ID NO:14:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 17 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:    -      Gly Tyr Lys Arg Lys Phe His Glu - # Lys His His Ser His Arg Gly    Tyr    #   15    -      Arg    - (2) INFORMATION FOR SEQ ID NO:15:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 18 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:    -      Lys Arg His His Gly Tyr Lys Arg - # Lys Phe His Glu Lys His His    Ser    #   15    -      His Arg    - (2) INFORMATION FOR SEQ ID NO:16:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 14 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:    -      Gly Tyr Lys Arg Lys Phe His Glu - # Lys His His Ser His Arg    #   10    - (2) INFORMATION FOR SEQ ID NO:17:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 15 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:    -      Lys Arg His His Gly Tyr Lys Arg - # Lys Phe His Glu Lys His His    #   15    - (2) INFORMATION FOR SEQ ID NO:18:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:    -      Ala Lys Arg His His Gly Tyr Lys - # Arg Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:19:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 11 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:    -      Lys Arg His His Gly Tyr Lys Arg - # Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:20:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 11 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    - 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    (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:    -      Lys Arg His His Gly Tyr Lys Arg - # Lys Phe    #   10    - (2) INFORMATION FOR SEQ ID NO:24:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:    -      Ala Lys Arg Phe His Gly Tyr Lys - # Arg Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:25:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:    -      Ala Lys Arg His Phe Gly Tyr Lys - # Arg Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:26:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:    -      Ala Lys Arg His His Gly Tyr Lys - # Arg Lys Phe Phe    #   10    - (2) INFORMATION FOR SEQ ID NO:27:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:    -      Ala Lys Arg Phe Phe Gly Tyr Lys - # Arg Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:28:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:    -      Ala Lys Arg Phe Phe Gly Tyr Lys - # Arg Lys Phe Phe    #   10    - (2) INFORMATION FOR SEQ ID NO:29:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:    -      Ala Lys Arg His His Lys Tyr Lys - # Arg Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:30:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:    -      Ala Lys Arg His His Gly Tyr His - # Arg Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:31:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:    -      Ala Lys Arg His His Lys Tyr His - # Arg Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:32:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:    -      Ala Lys Arg His His Gly Tyr Phe - # Arg Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:33:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:    -      Ala Lys Arg Leu Leu Gly Tyr Lys - # Arg Lys Phe Leu    #   10    - (2) INFORMATION FOR SEQ ID NO:34:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:    -      Ala Lys Arg Tyr Tyr Gly Tyr Lys - # Arg Lys Phe Tyr    #   10    - (2) INFORMATION FOR SEQ ID NO:35:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:    -      Ala Gln Arg His His Gly Tyr Lys - # Arg Gln Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:36:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:    -      Ala Lys Gln His His Gly Tyr Lys - # Gln Lys Phe His    #   10    - (2) INFORMATION FOR SEQ ID NO:37:    -      (i) SEQUENCE CHARACTERISTICS:    #acids    (A) LENGTH: 12 amino              (B) TYPE: amino acid              (C) STRANDEDNESS:              (D) TOPOLOGY: linear    -     (ii) MOLECULE TYPE: peptide    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:    -      Ala Gln Gln His His Gly Tyr Lys - # Gln Gln Phe His    #   10    __________________________________________________________________________

We claim:
 1. A composition for treating a fungal or bacterial infectioncomprising one or more peptides wherein a peptide has an amino addsequence, of at least nine amino acids, selected from the group of aminoacid sequences consisting of:a) the amino acid sequence of peptide 113as set forth in SEQ ID NO: 18 where the glycine at position 6 isreplaced by lysine, arginine or another basic amino acid; b) the aminoacid sequence of peptide 113 as set forth in SEQ ID NO: 18 where thelysine at position 8 is replaced by histidine, phenylalanine or anotherhydrophobic amino acid; c) the amino acid sequence of peptide 113 as setforth in SEQ ID NO: 18 where at least on of the histidines at position4, 5 and 12 is replaced by phenylalanine, tyrosine, leucine or anotherhydrophobic amino acid; d) the amino acid sequence of peptide 113 as setforth in SEQ ID NO: 18 where at least one of the lysines at positions 2and 10 are replaced by glutamine, arginine or by another basic aminoacid; e) the amino acid sequence of peptide 113 as set forth in SEQ IDNO: 18 where at least one of the arginines at positions 3 and 9 isreplaced by glutamine, lysine, or by another basic amino acid; and f)any combination of peptides having the amino acid replacements ofpreceding sections a)-e) with the exception that glutamine or any othernon-basic amino acid cannot simultaneously occupy positions 2, 3, 9 and10 of the amino acid sequence.
 2. A composition of claim 1 wherein theamino acid sequence of said peptide is selected from the group of aminoacid sequences consisting of:a) the amino acid sequence of peptide113-F4 as set forth in SEQ ID NO:24; b) the amino acid sequence ofpeptide 113-F5 as set forth in SEQ ID NO:25; c) the amino acid sequenceof peptide 113-F12 as set forth in SEQ ID NO:26; d) the amino acidsequence of peptide 113-F4.5 as set forth in SEQ ID NO:27; e) the aminoacid sequence of peptide 113-F4.5.12 as set forth in SEQ ID NO:28; f)the amino acid sequence of peptide 113-K6 as set forth in SEQ ID NO:29;g) the amino acid sequence of peptide 113-H8 as set forth in SEQ IDNO:30; h) the amino acid sequence of peptide 113-K6H8 as set forth inSEQ ID NO:31; i) the amino acid sequence of peptide 113-F8 as set forthin SEQ ID NO:32; j) the amino acid sequence of peptide 113-L4.5.12 asset forth in SEQ ID NO:33; k) the amino acid sequence of peptide113-Y4.5. 12 as set forth in SEQ ID NO:34; l) the amino acid sequence ofpeptide 113-Q2. 10 as set forth in SEQ ID NO:35; and m) the amino acidsequence of peptide 113-Q3.9 as set forth in SEQ ID NO:36.
 3. Acomposition of claim 1 wherein the peptide has a modification comprisingthe addition of at least one substituent to either the N-terminus, theC-terminus, or to both the N-terminus and C-terminus of said peptide. 4.A composition of claim 3 wherein at least one of said modifications ofsaid peptide is selected from the group consisting of:a) an acetyl or acarbamyl addition at the N-terminus; and b) an amide addition at theC-terminus.
 5. A composition for treating a fungal or bacterialinfection comprising one or more peptides having a modificationcomprising the addition of at least one substituent to either theN-terminus, the C-terminus, or to both the N-terminus and C-terminus ofsaid peptide, wherein said peptide has an amino acid sequence, of atleast nine amino acids, selected from the group of amino acid sequencesconsisting of:a) the amino acid sequence of peptide 113 as set forth inSEQ ID NO: 18; b) the amino acid sequence of histatin 11 as set forth inSEQ ID NO: 11; c) the amino acid sequence of peptide 129 as set forth inSEQ ID NO:23; d) the amino acid sequence of peptide 117 as set forth inSEQ ID NO: 19; e) the amino acid sequence of peptide 118 as set forth inSEQ ID NO:20; f) the amino acid sequence of peptide 119 as set forth inSEQ ID NO:21; and g) the amino acid sequence of pepitide 120 as setforth in SEQ ID NO:22.
 6. A composition of claim 5 wherein at least oneof said modifications of said peptide is selected from the groupconsisting of:a) an acetyl or a carbamyl addition at the N-terminus; andb) an amide addition at the C-terminus.
 7. A peptide having an aminoacid sequence, of at least nine amino acids, selected from the group ofamino acid sequences consisting of:a) the amino acid sequence of peptide113 as set forth in SEQ ID NO: 18 where the glycine at position 6 isreplaced by lysine, arginine or another basic amino acid; b) the aminoacid sequence of peptide 113 as set forth in SEQ ID NO: 18 where thelysine at position 8 is replaced by histidine, phenylalanine or anotherhydrophobic amino acid; c) the amino acid sequence of peptide 113 as setforth in SEQ ID NO: 18 where at least on of the histidines at position4, 5 and 12 is replaced by phenylalanine, tyrosine, leucine or anotherhydrophobic amino acid; d) the amino acid sequence of peptide 113 as setforth in SEQ ID NO: 18 where at least one of the lysines at positions 2and 10 are replaced by glutamine, arginine or by another basic aminoacid; and e) the amino acid sequence of peptide 113 as set forth in SEQID NO: 18 where at least one of the arginines at positions 3 and 9 isreplaced by glutamine, lysine, or by another basic amino acid.
 8. Thepeptide of claim 7 selected from the group of amino acid sequencesconsisting of:a) the amino acid sequence of peptide 113-F4 as set forthin SEQ ID NO:24; b) the amino acid sequence of pepdide 113-F5 as setforth in SEQ ID NO:25; c) the amino acid sequence of peptide 113-F12 asset forth in SEQ ID NO:26; d) the amino acid sequence of peptide113-F4.5 as set forth in SEQ ID NO:27; e) the amino acid sequence ofpeptide 113-F4.5.12 as set forth in SEQ ID NO:28; f) the amino acidsequence of peptide 113-K6 as set forth in SEQ ID NO:29; g) the aminoacid sequence of peptide 113-H8 as set forth in SEQ ID NO:30; h) theamino acid sequence of peptide 113-K6H8 as set forth in SEQ ID NO:31; i)the amino acid sequence of peptide 113-F8 as set forth in SEQ ID NO:32;j) the amino acid sequence of peptide 113-L4.5.12 as set forth in SEQ IDNO:33; k) the amino acid sequence of peptide 113-Y4.5.12 as set forth inSEQ ID NO:34; l) the amino acid sequence of peptide 113-Q2. 10 as setforth in SEQ ID NO:35; m) the amino acid sequence of peptide 113-Q3.9 asset forth in SEQ ID NO:36; and n) the amino acid sequence of peptide113-Q2.3.9.10 as set forth in SEQ ID NO:37.
 9. The peptide of claim 7wherein the peptide has a modification comprising the addition of atleast one substituent to either the N-terminus, the C-terminus, or toboth the N-terminus and C-terminus of said peptide.
 10. A composition ofclaim 9 wherein at least one of said modifications of said peptide isselected from the group consisting of:a) an acetyl or a carbamyladdition at the N-terminus; and b) an amide addition at the C-terminus.11. A peptide having a modification comprising the addition of at leastone substituent to either the N-terminus, the C-terminus, or to both theN-terminus and C-terminus of said peptide, wherein said peptide has anamino acid sequence, of at least nine amino acids, selected from thegroup of amino acid sequences consisting of:a) the amino acid sequenceof peptide 113 as set forth in SEQ ID NO: 18; b) the amino acid sequenceof histatin 11 as set forth in SEQ ID NO:11; c) the amino acid sequenceof peptide 129 as set forth in SEQ ID NO:23; d) the amino acid sequenceof peptide 117 as set forth in SEQ ID NO:19; e) the amino acid sequenceof peptide 118 as set forth in SEQ ID NO:20; f) the amino acid sequenceof peptide 119 as set forth in SEQ ID NO:21; and g) the amino acidsequence of peptide 120 as set forth in SEQ ID NO:22.
 12. A compositionof claim 11 wherein at least one of said modifications of said peptideis selected from the group consisting of:a) an acetyl or a carbamyladdition at the N-terminus; and b) an amide addition at the C-terminus.13. A method for treating a fungal or bacterial infection in anindividual comprising administering to said individual a therapeuticallyeffective amount of one or more peptides having an amino acid sequence,of at least eight amino acids, selected from the group of amino acidsequences consisting of:a) the amino acid sequence of peptide 113 as setforth in SEQ ID NO: 18 where the glycine at position 6 is replaced bylysine, arginine or another basic amino acid; b) the amino acid sequenceof peptide 113 as set forth in SEQ ID NO: 18 where the lysine atposition 8 is replaced by histidine, phenylalanine or anotherhydrophobic amino acid; c) the amino acid sequence of peptide 113 as setforth in SEQ ID NO: 18 where at least on of the histidines at position4, 5 and 12 is replaced by phenylalanine, tyrosine, leucine or anotherhydrophobic amino acid; d) the amino acid sequence of peptide 113 as setforth in SEQ ID NO: 18 where at least one of the lysines at positions 2and 10 are replaced by glutamine, arginine or by another basic aminoacid; e) the amino acid sequence of peptide 1 13 as set forth in SEQ IDNO: 18 where at least one of the arginines at positions 3 and 9 isreplaced by glutamine, lysine, or by another basic amino acid; and f)any combination of the amino acid replacements of preceding sectionsa)-e) with the exception that glutamine or any other non-basic aminoacid cannot simultaneously occupy positions 2, 3, 9 and 10 of the aminoacid sequence.
 14. A method for treating a fungal or bacterial infectionof claim 13 wherein the amino acid sequence of said one or more peptidesis selected from the group of amino acid sequences consisting of:a) theamino acid sequence of peptide 113-F4 as set forth in SEQ ID NO:24; b)the amino acid sequence of peptide 113-FS as set forth in SEQ ID NO:25;c) the amino acid sequence of peptide 113-Fl12 as set forth in SEQ IDNO:26; d) the amino acid sequence of peptide 113-F4.5 as set forth inSEQ ID NO:27; e) the amino acid sequence of peptide 113-F4.5.12 as setforth in SEQ ID NO:28; f) the amino acid sequence of peptide 113-K6 asset forth in SEQ ID NO:29; g) the amino acid sequence of peptide 113-H8as set forth in SEQ ID NO:30; h) the amino acid sequence of peptide113-K6H8 as set forth in SEQ ID NO:31; i) the amino acid sequence ofpeptide 113-F8 as set forth in SEQ ID NO:32; j) the amino acid sequenceof peptide 113-L4.5. 12 as set forth in SEQ ID NO:33; k) the amino acidsequence of peptide 113-Y4.5.12 as set forth in SEQ ID NO:34; l) theamino acid sequence of peptide 113-Q2. 10 as set forth in SEQ ID NO:35;and m) the amino acid sequence of peptide 113-Q3.9 as set forth in SEQID NO:36.
 15. A method for treating a fungal or bacterial infection ofclaim 13 wherein the peptide has a modification comprising the additionof at least one substituent to either the N-terminus, the C-terminus, orto both the N-terminus and C-terminus of said peptide.
 16. A method fortreating a fungal or bacterial infection of claim 15 wherein at leastone of said modifications of said peptide is selected from the groupconsisting of:a) an acetyl or a carbamyl addition at the N-terminus; andb) an amide addition at the C-terminus.
 17. A method for treating afungal or bacterial infection of claim 13 wherein said fungal orbacterial infection is selected from the group consisting of:a) aninfection of the oral cavity; b) an infection of the vagina; c) aninfection of the urethra; d) an infection of the ear; e) an infection ofthe skin; f) a respiratory infection; g) a mucosal infection; h) anophthalmic infection; and i) a systemic infection.
 18. A method fortreating a fungal or bacterial infection of claim 17 wherein the fungusor bacterium is selected from the group consisting of:a) Candidaalbicans; b) Actinomyces actinomycetemcomitans; c) Actinomyces viscosus;d) Bacteroides forsythus; e) Bacteriodes fragilis; f) Bacteriodesgracilis; g) Bacteriodes ureolyticus; h) Campylobacter concisus; i)Campylobacter rectus; j) Campylobacter showae; k) Campylobactersputorum; l) Capnocytophaga gingivalis; m) Capnocytophaga ochracea; n)Capnocytophaga sputigena; o) Clostridium histolyticum; p) Eikenellacorrodens; q) Eubacterium nodatum; r) Fusobacterium nucleatum; s)Fusobacterium periodonticum; t) Peptostreptococcus micros; u)Porphyromonas endodontalis; v) Porphyromonas gingivalis; w) Prevotellaintermedia; x) Prevotella nigrescens; y) Propionibacterium acnes; z)Pseudomonas aeruginosa; aa) Selenomonas noxia; bb) Staphylococcusaureus; cc) Streptococcus constellatus; dd) Streptococcus gordonii; ee)Streptococcus intermedius; ff) Streptococcus mutans; gg) Streptococcusoralis; hh) Streptococcus pneumonia; ii) Streptococcus sanguis; kk)Treponema denticola; ll) Treponema pectinovorum; mm) Treponemasocranskii; nn) Veillonella parvula; and oo) Wolinella succinogenes. 19.A method for treating a fungal or bacterial infection in an individualcomprising administering to said individual a therapeutically effectiveamount of one or more peptides having a modification comprising theaddition of at least one substituent to either the N-termninus, theC-terminus, or to both the N-terminus and C-terminus of said peptidewherein said peptide has an amino acid sequence, of at least eight aminoacids, selected from the group of amino acid sequences consisting of:a)the amino acid sequence of peptide 113 as set forth in SEQ ID NO:18; b)the amino acid sequence of histatin 11 as set forth in SEQ ID NO:11; c)the amino acid sequence of peptide 129 as set forth in SEQ ID NO:23; d)the amino acid sequence of peptide 117 as set forth in SEQ ID NO:19; e)the amino acid sequence of peptide 118 as set forth in SEQ ID NO:20; f)the amino acid sequence of peptide 119 as set forth in SEQ ID NO:21; andg) the amino acid sequence of peptide 120 as set forth in SEQ ID NO:22.20. A method for treating a fungal or bacterial infection of claim 19wherein at least one of said modifications of said peptide is selectedfrom the group consisting of:a) an acetyl or a carbamyl addition at theN-terminus; and b) an amide addition at the C-terminus.
 21. A method fortreating a fungal or bacterial infection of claim 19 wherein said fungalor bacterial infection is selected from the group consisting of:a) aninfection of the oral cavity; b) an infection of the vagina; c) aninfection of the urethra; d) an infection of the ear; e) an infection ofthe skin; f) a respiratory infection; g) a mucosal infection; h) anophthalmic infection; and i) a systemic infection.
 22. A method fortreating a fungal of bacterial infection of claim 21 wherein the fungusor bacterium is selected from the group consisting of:a) Candidaalbicans; b) Actinomyces actinomycetemcomitans; c) Actinomyces viscosus;d) Bacteroides forsythus; e) Bacteroides fragilis; d) Bacteroidesgraciclis; f) Bacteroides ureolyticus; g) Campylobacter concisus; h)Campylobacter rectus; i) Campylobacter showae; j) Campylobactersputorum; k) Capnocytophaga gingivalis; I) Capnocytophaga ochracea; m)Capnocytophaga sputigena; n) Clostridium histolyticum; o) Eikenellacorrodens; p) Eubacterium nodatum; q) Fusobacterium nucleatum; s)Fusobacterium periodonticum; t) Peptostreptococcus micros; u)Porphyromonas endodontalis; v) Porphyromonas gingivalis; w) Prevotellaintermedia; x) Prevotella nigrescens; y) Propionobacterium acnes; z)Pseudomonas aeruginosa; aa) Selenomonas noxia; bb) Staphylococcusaureus; cc) Streptococcus constellatus; dd) Streptococcus gordonli; ee)Streptococcus intermedius; ff) Streptococcus mutans; gg) Streptococcusoralis; hh) Streptococcus pneumonia; ii) Streptococcus sanguis; jj)Treponoma denticola; kk) Treponoma pectinovorum; ll) Treponomasocranskii; mm) Veillonella parvula; and nn) Wolinella succinogenes.